The outbreak of an unexplained adult respiratory distress syndrome in the southwestern region of the U.S. around May of 1993 is attributed to a novel hantavirus (tentatively named the Four Corners Hantavirus). Initial disease stages are marked by flu-like symptoms that last from 1 to 4 days followed by acute pulmonary edema that can result in death in approximately 60% of the diagnosed cases. The majority of the deaths have occurred in New Mexico. In the past, Hantavirus strains (Hantaan, Korean) were common to Asia and Europe, and associated with fever, hemorrhaging, cardiovascular instability, shock, renal failure and death in about 7% of the cases. The long-term goal of this work is to understand the biochemistry and cell biology of hantavirus replication and transcription. Hantaviruses are enveloped, spherical, negative-stranded RNA viruses. Family members have a tripartite segmented genome composed of S (encodes N protein or nonnucleocapsid), M (encodes G1, G2 proteins or envelope proteins) and L (encodes RNA-dependent RNA polymerase) segments. Our studies focus on the Hantaan and Four Corners viruses RNA dependent RNA polymerase, RDRP, the key enzyme in hantaviral mediated transcription and replication. The enzymatic activities of the Hantaan RDRP from virions, infected Vero cell lines, and a recombinant yeast system will be examined by three complementary approaches: (1) direct examination of RDRP in vitro; (2) template requirements in vivo; (3) interaction of the hanta- virus N protein and RDRP. Our working hypothesis is that the RDRP will minimally have three activities: (1) transcription of the negative strand vRNA to mRNA; (2) replication of vRNA to cRNA; and (3) replication of the cRNA to vRNA. In addition, the N protein is proposed to be involved in directing the RDRP toward transcription or replication. The outbreak of this novel hantavirus in the USA indicates more virulent strains with atypical symptoms may exist in nature. Knowledge of the activities of the RDRP would hopefully contribute to the design of antihantavirus drugs and therapies for all hantaviral strains regardless of the associated disease.